Novel phosphorylated phosphonium ylids

ABSTRACT

Novel phosphorylated phosphonium ylids are prepared by reacting a monosubstituted phosphonium ylid with an appropriately disubstituted phosphoryl halide or thiophosphoryl halide. The novel ylids are useful as intermediates in the preparation of phosphonic acid or thiophosphonic acid derivatives therefrom and as intermediates for the preparation of insecticides, herbicides, oil additives and 5&#39;&#39;,6&#39;&#39;-dideoxyhexofuranosylnucleoside 6&#39;&#39;phosphonic acid.

United States Patent [191 Moffatt et a].

NOVEL PHOSPHORYLATED PHOSPHONIUM YLIDS Inventors: John G. Moft'att; Gordon H. Jones, both of Los Altos, Calif.

Assignee: Syntex (U.S.A) Inc., Palo Alto,

Calif.

Filed: Oct. 15, 1971 Appl. No.: 189,562

Related US. Application Data Division of Ser. No. 709,234, Feb. 29. 1968. Pat. No.

3,662.03 l, which is a continuation-in-part of Ser. No. 654,056, June l8. I967, abandoned.

US. Cl 260/21L5 R; 260/954; 7l/86; 71/87; 260/956; l95/28 N; 252/466;

260/968; 260/247.7 D; 260/252; 424/200; 260/254; 260/256.4 E; 424/l80; 260/293.4

B; 260/293.4 R; 424/203; 260/502.4 R; 260/55l P; 424/219; 260/927 R; 260/932 Int. Cl... C07d 51/50; C07d l05/04; C07f 9/54 [451 Apr. 15, 1975 [58] Field of Search 260/2l l.5 R

[56] References Cited UNITED STATES PATENTS 3,583.974 6/l97l Jones et al. 260/21 1.5 R

Primary Examiner-Johnnie R. Brown Attorney, Agent, or Firm-Lawrence S. Squires; William B. Walker 8 Claims, No Drawings wherein each of R. R and R" is lower alkyl. aryl or substituted aryl:

R. R and R together are tri-N-piperidyl. tri-N- morpholinyl or tricyelohesyl;

R is hydrogen. lower alkyl eyclohesy l. aryl. or substituted al'yl.

Y is oxygen or sulfur.

each of 7. and I. is the group ()R'. SR

or NR R" in which each of R and R is lower alkyl. lower alkenyl. aryl or substituted aryl. and each of R and R" is low er alkyl. of aryl; and

Z and Z" together are the group in which R" is alkylene or arylene.

The term "lower alkyl" means a straight or branched chain hydrocarbon group containing from l to 6 carbon atoms. inclusive. such as methyl. ethyl. n-propyl. Lbutyl. t-butyl. and the like. The term lower alkenyl" means an alkyl group containing one carboncarbon double bond such as allyl and the like. The term aryl" means a hydrocarbon group consisting of one or more aromatic rings and containing from 6 to l2 carbon atoms. inclusive. such as phenyl. benzyl. o-tolyl. mtolyl. p-tolyl. 3.5-xylyl. pentamethylphenyl. naphthyl. and the like. The term "substituted aryl" means an aryl group hming one or more halo. nitro. alkoxy. or dialkylamino substituents in the aromatic ring such as pchlorobenzyl. p-bromobenzyl. 2.4.(i-trichlorophenyl. p-nitrophenyl. p-nitrobenzyl. p-anisyl. pmethoxybenzyl. p dimethylaminophenyl. and the like. The term "lower alkylene" means the group -(('H. i,,- in which n has a value of from Z to 4. inclusive. such as ethylene. trimethy lene and tetramethylene. said group can be further substituted with one or more alkyl or arylgroups such as in 2.Z-dimethyltrimethylene. l.2- diphenylethylenc and the like. The terin "arylene" means an aryl group ha\ing two sites of attachment such as ophenylene and the like.

till

A primary object of the present intention is to provide a new class of phosphorylated phosphonium ylids which can be reacted with a wide variety of aldehydes and ketones. thereby providing unsaturated phosphonate or thiophosphonate derivatives thereof. Another object ofthe invention is to provide a process for reacting the novel phosphorylated phosphonium ylid with a nucleoside 5'-aldehyde to form the corresponding 5'.b- '-dideox vhex-5'-enofuranosylnucleoside phosphonate. The latter unsaturated nucleosidc is catalytically hydrogenated or chemically reduced and then converted to a corresponding 5'.h'-dideosyhexofuranosylnucleoside b'-phosphonic acid by hydrolysis. hydrogenolysis. anionic dcalkylation. or enzymatic ac tion or combinations thereof.

The novel phosphorylated phosphonium ylids of For mula (A) are prepared according to the following reaction:

wherein X is ehloro or bromo; and all other substituents are as defined hereinabove.

In the practice of the above sequence. a monosubstituted phosphonium ylid (l) is condensed under substantially anhydrous conditions with an appropriately disubstituted phosphoryl halide or thiophosphoryl halide ill) in a non-reactive organic solvent such as tetrahydrofuran. dioxane. dimethylformamide. dimethyl sulfoxide. benzene. diethyl ether. hexane. and the like. and mixtures thereof. at a temperature of about 0C to the reflux temperature of the sohent. for a period of about V2 to about 12 hours. Preferably. the condensation is performed in diethyl ether. hexane. tetrahydrofuran. benzene. or mixtures thereof. with an appropriately disubstituted phosphoryl chloride or thiophos phoryl chloride (ll). ie wherein X is chloro. Furthermore. reactions of the monosubstituted phosphonium ylid (I). wherein R is hydrogen. alkyl or cyclohexyl. are preferably performed at room temperature fora period of about l5 minutes to about 1 hour; and reactions of the monosubstituted phosphonium ylid (I). wherein R is aryl or substituted aryl are preferably performed at the reflux temperature of the solvent for a period of about 2 hours or longer.

Although the molar proportion of the nionosubstituted phosphonium ylid (ll to the disubstituted phosphoryl halide or thiophosphoryl halide (II) is not critical. a preferred embodiment of two moles of the mono substituted phosphonium ylid per mole of the disubstituted phosphoryl halide or thiophosphoryl halide (ll) is convenient.

In the practice of the aboie sequence. the reaction is advantageously performed in the presence of an inert atmosphere such as a nitrogen atmosphere. an argon atmosphere. and the like. In addition. the monosubstituted phosphonium ylid (I) is generated in situ by con ventional techniques known to those skilled in the art.

Included among the monosuhstituted phosphonium ylids (l) which can be condensed with the disubstituted phosphoryl halide or thiophosphoryl halide (ll) are methylenetrialkylt including cycloalkyl lphosphoranes such as methylenetridn-butyl lphosphorane. methylenetrimethylphosphoranc. niethylenetricyclohexylphosphorane. and the like; methylenealkylarylphospho runes such as methyleneethyldipheny lphosphoranc. in cthy lenemethy ldiphenylphosphorane. nicthy lencdiphcnyl-t-butylphosphorane. and the like; mcthylcnctriaryh phosphoranes such as methylenetriphcnylphosphorane. methylenetri-p-tolylphosphoranc. methylenetri p-anisylphosphorane. and the like: alkylidcnctrialkylphosphoranes such as cthy lidcne-t nbutyllphosphorane. and the like. alkylidencalkylarylphosphoranes such as ethylidenemethyldiphenylphosphorane. and the like; alkylidenetriarylphosphoranes such as cthylidcnetriphenylphosphorane. propylidenet riphenylphosphorane, butylidenetriphenylphospho rane. penty lidenetripheny lphosphorane. cyclohexylmcthylcnetriphcnylphosphorane. B-phenylethylidenetriphenylphosphorane. 3-niethylbutylidenetriphenylphosphorane. and the like; arylmcthylenetrialkylphospho rancs such as hemylidenetrimethylphosphoranc. benzylidcnetricyclohcXylphosphorane. and the like: arylmc thylenctriarylphosphorancs such as henzylidenctri phcnylphosphoranc. p-nitrobcnzylidenctriphenylphosphorane. p-methoxybenzylidenetriphenylphosphorane. bcnv'ylidenediphenyl-p-diinethylaminophenylphospho ranc. and the like: and methylenetri-N-morpholinylphosphorane. methylenetri-N-piperidylphosphorane. and the like.

Additionally. other monosubstituted phosphonium ylids I l I are prepared according to conventional procedures as described by S. Trippett, Advances in Organic Chemistry. [ntersciencc Publishing Co. New York 1 1960), Vol. 1. pages 83-102; 5. Trippett. Quur lr'rl Review, Vol. l6-17. pages 4(JU44U I 1962-1963); AW. Johnson. "Ylid Chemistry. Academic Press. New York (19661; and A. Maerckcr. Organic Reactions". \'ol. 14. John Wiiey & Sons. lnc.. New York l l9b5 I.

lncluded among the disuhstituted phosphoryl halides or thiophosphoryl halides (ll) which can be used to prepare the note] phosphorylated phosphonium ylids (Al are disubstituted phosphorochloridates such as dimethyl phosphorochloridate. di-ethyl phosphorochlori date. diall \'l phosphorochloridate. di-iso-butyl phosphorochloridate. diphenyl phosphorochloridate. dio tolyl phosphorochloridatc. di-m-tolyl phosphorochlori date. di-p-tolyl phosphorochloridate. o-phcnylene phosphorochloridate. trimethylene phosphorochloridate. di-3 .S-xy lyl phosphorochloridate. di-t pnitrophenyll phosphorochloridate. 1,1 diphenylethylene phosphorochloridate. 1.2 dimethyltrimethylene phosphorochloridatc. ethyl pnitrophenyl phosphorochloridate. dibenzyl phosphorochloridatc. di-tniiitrtibeii/yli phosphorochloridate. di-lpentaniethylphenylI phosphorochloridate. di-(pbromobenzyl) phosphorochloridatc. and the like; disubstituted phosphorobromidates such as dimethyl phosphorobromidate. diphenyl phosphorobromidate. methyl phenyl phosphorobroniidate. o-phenylene phosphorohroniidatc. and the like. disubstitutcd chloridothioutes such as ().()-diethyl phiisphorochloridothioatc. ().()-dimcthyl phosphtirochloridothioatc. 0.0- diphenyl phosphorochloridothioate. 0.0di(p' chlorobenzyll phosphorochloridothioate. .S diethyl phosphorochloridothioate. Oethyl-O-p-nitrophenyl phosphorochloridothioate. O-methyl-O-2.4 5- trichlorophenyl phosphorochloridothioate. and the like; disubstituted chloridodithioates such as 5.5- diethyl phosphorochloridodithioate. S.S-dibutyl phosphorochloridodithioate. and the like; disubstituted chloridotrithioatc such as diethyl phosphorochloridotrithioate. and the like. disubstituted phosphorobromidothioates such as 0.0-diethyl phosphorobromidothioate. Olldiphenyl phosphorobromidothioate and the like. disubstituted phosphorodiamidic chlo rides such as tetraethylphosphorodiamidic chloride. phosphorodimorpholidic chloride. N.N'-dimethylphosphorodianalidic chloride. tetramethyl phosphorodiamidic chloride. and the like; disubstituted phosphorodianiidic bromides such as phosphorodimorpholidic bromide and the like; mixed disubstituted phosphoramidochloridates such as O-phenyl N.N-diethylphosphoramidochloridate. O-ethyl N.N-diethylphosphoramidochloridate. O-isopropyl N.N-dimethylphosphoramidochloridate. and the like; mixed disubstituted phosphoramidochloridothioates such as S-butyl N,N- dicthylphosphoramidochloridothioate. O-ethyl N.N- diethylphosphoramidochloridothioate. O[2,4.5- trichlorophenyll N.N-dimethylphosphoramidochloridothioate. and the like.

Additionally. other disubstituted phosphoryl halides or thiophosphoryl halides (ll) are obtained by convert tional techniques as described by UN. Kosolapoff. Organophosphorus Compounds. John Wiley & Sons, lnc.. New York l 1 51 Chapters 9 and 10. For example. the disubstitutcd phosphoryl halides or thiophosphoryl halides. i.e when Z and Z together are the group (ORl or 15R"): are prepared by adding 2 moles of a hydroxy or mercapto containing compound to 1 mole of phosphoryl chloride. phosphoryl bromide. thiophosphoryl chloride. or thiophosphoryl bromide in an essentially anhydrous non-reactive solvent such as chloroform. benzene. ether. tetrahydrofuran. dioxane. or mixtures thereof. and the like. at a temperature of from about room temperature to the reflux temperature of the solvent for a period of about 1 to 12 hours. as shown by the following equations and as described on pages 211-213 of the latter reference:

H ix. 211 011 xnomn HX R" being lower alkyl and all other substituents being as defined hcreinabo e. When the reaction is per formed at the lower temperature. i.e. about room temperature. it is convenient to use the moles of teritary base such as 2.4.6collidine. 2,6-lutidine. N.N dimethylaniline and the like to remove the liberated acid HX. Included among the hydroxy containing compounds which can be reacted with the phosphorus halide y the are alcohols such as methanol. ethanol. n-propanol, iso-butanol. n-amyl alcohol. and the like; phenols such as phenol. o-cresol. ni-cresol. p-cresol. p-cresol. 3.5- xylenol. pcntamethyl phenol. lchlorophenol. and the like; and mercaptans such as methanethiol. ethanethiol. n-propanethiol. and the like.

Other disubstituted phosphoryl halides and thiophos phoryl halides. i.e. wherein Z' and Z" together are (SR)- in which R is aryl or substituted aryl are prepared by first adding 3 moles of the sodium salt of a thiophenol to I mole of phosphoryl chloride. phosphoryl bromide. thiophosphoryl chloride. or thiophosphoryl bromide. to obtain a trithioester and second treating the trithioester with one mole of acetyl chloride or acetyl bromide as shown in the following equa tions and as described on page 218 of the latter reference.

R"" being aryl or substituted aryl; and all other substituents are as defined hereinabove. Included among the thiophenols which can be reacted in the above manner. are thiopheno]. thio-o-cresol. thio-p-cresol. and the like.

The disubstituted phosphorodiamidic halides. i.e. wherein each of Z and Z is the group Y ll PX; 4HN

WC. (J

all substituents being as defined hereinabove. Included among the secondary amines which can be reacted with the phosphorus halide Y l x.

are piperidine. morpholine; dialkyl amines such as dimethylamine. diethylamine. di-n-propylamine. and the like: diaryl amines such as diphenylamine and the like. and mixed alkyl aryl amines such as N-methylaniline and the like.

The mixed disubstituted phosphoryl halides or thiophosphoryl halides (II I. i.e. wherein each of Z and 2" are different. are prepared by varying the molar proportions of reactants and proceeding in a two-step reaction sequence. as shown by the following equations:

each of R andR being lower alkyl'. and each of R and R being aryl; and all other substituents being as described hereinabove.

In addition. the disubstituted phosphoryl halides or thiophosphoryl halides. i.e. wherein Z' and Z together are the group are prepared by adding one mole of a dihydroxy containing compound. a dimercapto containing compound or a monohydroxy monomercapto compound to one mole of phosphoryl chloride. phosphoryl bromide. thiophosphoryl chloride. or thiophosphory] bromide under essentially the same anhydrous conditions as described above. and as shown by the following equatrons:

are dihydroxy compounds such as ethylene glycol. trimethylene glycol. tetramethylene glycol. 2.2- dimethyltrimethylene glycol. 1.2-diphenylethylene glycol. catechol. and the like; dimercapto compounds such as l.2-ethanedithiol. l.3-propanedithiol. I.4- butaneclithiol. l.2-benzenedithiol. and the like; and monohydroxy monomercapto compounds such as monothiis lower alkyl or cyclohexyl; each of is the group OR wherein R" Z" and Z or NR R" in which R" is aryl or substituted aryl; and all other substituents being as defined hereinabove.

In the practice of this alternative method. a trisubstituted phosphine lllli is allowed to react under substantially anhydrous conditions with an appropriately disubstituted halomcthylphosphonic acid or halomethylphosphonothioic acid (IV! in a non-reactive organic soltent such as tetrahydrofuran. dioxane. benzene. dimethylformamide. and the like. or mixtures thereof. at room temperature to the reflux temperature of the solvent for a period of about 15 minutes to 24 hours. to afford a phosphorylated phosphonium halide salt (V1. The latter salt (Y) is converted to a corresponding phosphorylated phosphonium ylid (A') by treatment with an aqueous solution of a base. said solution o tionally containing an organic solvent such as a lower monohydric alcohol such as methanol. ethanol and the like; a cyclic water-miscible ether such as dioxane. tet rahydrofuran and the like. Bases particularly useful for this purpose are potassium hydroxide. sodium hydroxide. sodium ethoxide. sodium carbonate. pyridine. and the like. The com ersion is effected at room temperature for a period of 5 minutes to 24 hours. a period of l5 minutes being preferred.

The thus-obtained novel ylid IN) is alkylated. if desired. by treatment with a halide of the formula R" X in a non-reactive organic solvent such as ethyl acetate. benzene. dioxane. dimethylformamide and the like. at an elevated temperature. cg. the reflux temperature of the solvent for a period of about l5 minutes to 3 hours to afford a corresponding alkylated phosphorylated phosphonium salt (VI). The latter salt (V!) is con- \erted to a corresponding ylid LA") by treatment with base as described hereinabme for the unalkylated salt I l l he trlsuhstituted phosphine t Ill 1 hich can be used to prepare some of the no\ cl phosphorylated phosphoniuin ylids IA and A") are described in the literature cited above.

The disubstituted halomethylphosphonic acids or haIomethylphosphonothioic acids t l\ l are prepared b adding a phenol. a secondary amine. or combinations thereof. in a stepwise manner. to chloromethylphosphonic acid dichloride. bromomethylphosphonic acid dichloride. chloromethylphosphonothioic dichloride. or bromomethylphosphonothioic dichloride. bromomethylphosphonic acid dibromide. bromomethylphosphonothioic acid dibromide. and the like. either alone or in the presence of a non-reactive organic solvent such as tetrahydrofuran. dioxane. benzene. or the like. or mixtures thereof. at reflux for a period of about 4 to 12 hours. The molar proportions of materials are varied. and the reaction is to be per formed in a step-wise manner depending on the particular material HY) being prepared. by procedures such as described hereinabm e the preparation of the mixed disubstituted phosphoryl halides or thiophosphoryl halides (ll As a second alternative. some of the no\el phosphor ylate phosphorus ylids of the present invention. i.e. wherein Y is oxygen. are prepared according to the following reaction:

wherein all substituents are as defined hereinabove.

In the practice ofthe second alternative method. the monosubstituted phosphonium ylid tll is allowed to react under substantially anhydrous conditions with an appropriately tetrasubstituted pyrophosphate (VII) in a non-reactive organic solvent such as tetrahydrofuran. ether. benzene. n-hexane. and the like. or mixtures thereof. at room temperature to the reflux temperature of the solvent for a period of 15 minutes to about 3 hours.

The tetrasubstituted pyrophosphates tVll) are prepared by first hydrolyling the disubstituted phosphoryl halide or thiophosphoryl halide ill) in an aqueous media at reflux for a period of about one-half to two hours to afford an intermediary disubstituted phosphoric acid. and second condensing said disubstituted phosphoric acid in the presence of a carbodiimide such as dicyclohexylcarbodiimide. di-p-tolylcarbodiimide. and the like. in an essentially anhydrous non-reactive organic solvent such as benzene. ether. dioxane. and

the like. such as described by H. G. Khorana and A. R. Todd. J. Chem. $06.. 2157 (1956).

As a third alternative. some of the novel phosphorylated phosphonium ylids of the present invention. i.e. those of Formula (A) in which R is lower alkyl or cyclohexyl. are prepared according to the following reaction sequence:

all substituents being as defined hereinabove.

lil

in the practice of the third alternative method. the

novel unalkylated phosphorylated phosphonium ylid A wherein R is hydrogen]. is converted to the corresponding novel alkylated phosphorylated phosphonium ylid HA), wherein R is lower alkyl or cyclohexyl]. by treatment with a halide of the formula R"X followed by basic treatment with an aqueous solution of a base as described hereinabove in the first alternative method.

The phosphorylated phosphonium ylids (A) are valuable intermediates which can be reacted with a wide variety ofaldehydes and ketones. thereby providing unsaturated phosphonate and thiophosphonate derivatives thereof. Thus. the present invention provides a valuable synthetic route for the preparation of phosphonic acids and thiophosphonic acids therefrom. as shown by the following reaction sequence:

wherein each of is an aldehyde and ketone. respectively; R"' being hydrogen or R"; and all other substituents being as de fined herein.

In the practice of the latter reaction sequence. the phosphorylated phosphonium ylid (A) is allowed to react with a carbonyl compound of Formulas (VlllAl and (VlllB). respectively. either alone or in an inert organic solvent such as tetrahydrofuran. dioxane. dimeth ylformamide. dimethyl sulfoxide. methanol. ethanol. acetonitrile. or mixtures thereof. and the like. at a temperature of 25C to the reflux temperature of the solvent but preferably at about 25C for a period of from 1 to 48 hours. to form a corresponding afi-unsaturated phosphonate or thiophosphonate derivative tlX Any aldehyde. i.e.

6:0 or ketone, i.e.

can be reacted with the phosphorylated phosphonium ylids of the present invention to form a corresponding a,B-unsaturated phosphonate or thiophosphonate derivative thereof. i.e.

For example. the carbonyl compounds of Formulas (VlllA) and (VlllB) may be any aldehyde or ketone of the aliphatic. alicyclic. aromatic. or heterocyclic series.

included among the aliphatic. alicyclic and aromatic groups which R and R can represent are alkyl tin eluding saturated and unsaturated. straight and branched chain alkyl and cycloalkyl) and aryl (including alkaryl and aralkyl) groups. such as methyl, ethyl. propyl, isopropyl. n-butyl. sec-butyl. amyl. hexyl. heptyl. octyl. allyl, methallyl. cyclobutyl. cyclopentyl. cyclohexyl. methylcyclohexyl. cycloheptyl. cyclohexenyl. phenyl. tolyl, xylyl. benzyl. and the like, as well as fused ring structures. such as indanyl. indenyl. naphthyl. acenaphthyl, phenanthryl. and cyclopentanopolyhydrophenanthryl rings. and the like, all of which can either be unsubstituted or substituted with one or more noninterfering substituents. e.g.. hydroxyl groups; hydroxyl derivatives. such as alkoxy. e.g. methoxy and acyloxy. e.g. acetoxy groups; nitro groups; amino groups; alkylamino groups, such as methylamino. dimethylamino and diethylamino groups; halogen. e.g. fluorine or chlorine; carbonyl derivatives; such as enol ether. acetal and ketal groups. and the like.

The thus-obtained afi-unsaturated phosphonate in which R is arylene; and (IX i.e. wherein Y is oxygen. is catalytically hydrogeall other substituents being as defined hereinabove. nated at room temperature by conventional technique are valuable intermediates in the preparation of nusuch as in the presence of a palladium on an inert sup CleOSide 6'-ph0sphonie acids. For example, when port catalyst such as palladium-on-bariuni sulfate. 5 R in the general formula palladium-on-calcium carbonate and the like. in a lower alcoholic sol\ent such as methanol. ethanol and i the like. to form a corresponding saturated phospho- 0:0 nate (X).

Alternati ely. the afi-unsaturated phosphonate (IX) ll) is reduced by treatment with diimide at room temperag'ven mule llldehyda repmscn pumculur ture in an inert non-reactive solvent such as methanol. Cla of Subslllumd y mfurfuryl groups. i.e. those ethanol. ethyl acetate and the like. or mixtures thereof. humg [he Strucwms: for a period of about one to about 24 hours to afford the corresponding saturated phosphonate (X). l

The thus-obtained afi-unsaturated thiophosphonates 0:?) R 0:!) 12 (IX). ie wherein Y is sulfur. which adversely affects the efficiency of the palladium catalyst. as well as the y I I I afi-unsaturated phosphonate (IX) having one or more groups such as nitro. ally-l and the like. which would be simultaneously reduced. are reduced by the diimide method as described above to afford the corresponding saturated thiophosphonate and phosphonates (X).

Each of the Z and Z groups in the thus-obtained a.[isaturated phosphonate or thiophosphonate (X) is removed by hydrolysis. hydrogenolysis. anionic dealkylation. enzymatic action. or combinations thereof. under a variety of different conditions to afford the ufi-saturated phosphonic acid or phosphonothioic acid (XII The variety of conditions is dependent upon the nature of the Z and Z groups so that the removal of the first group and then a second group can be effected in a step-wise manner or the removal of both groups can be effected in a one-step procedure as will be dis cussed in more detail below.

Alternathely. the a./3unsaturated phosphonate or thiophosphonate (IX) is converted to the correspond ing u./3-unsaturated phosphonic acid (XI) by hydroly sis. hydrogenolysis. anionic dealkylation. enzymatic action. or combinations thereof. and the latter aB-unsaturated phosphonic acid or thiophosphonic acid (XI) is converted to saturated phosphonic acid or thiophosphonic acid (XII) as described hereinabove.

Furthermore. the phosphorylated phosphonium ylids having the formula: 4

RH R13 wherein R"-' is a substituted or unsubstituted pyrimidine or purine base. e.g. uracil-l-yl. cytosin-l-yl. 4-chloro l.2-dihydropyrimidin-Z-on-l-yl. 5brom0uracil-l-yl. 5' bromocytosinJ-yl. S-chlorouraciI-I-yl. 5 chl0rocytosinl-yl. S-iodouraciLl-yl, 5-iodocytosin-l-yl. 5fluorouracill-yl. 5-fluorocytosin-l-yl. thymin-l-yl, S-methylcytosinl-yl. 5-trifluoromethyluracil-l-yl. S-trifluoromethylcytosin-l-yl. 5-aminouracil-l-yl. S-aminocytosin-l-yl. 5- methylaminouracil-l-yl. 5-methylaminocytosin-l-yl. 5- hydroxyuraciH-yl. (v-azauracil-l-y'l. fi-azacytosin-l-yl. 4-chIoro-6-azal .Z-dihydropyrimidin-2-on-lyl. 6- azathymin-l-yl. hypoxanthin-Q-yl. adenin-Q-yl. 6- dirnethylaminopurin-Q-yl, 2chloroadenin-9-yl. 6- chloropurin-9-yl, 6-mercapt0purin-9-yl. guanin-9-yl. xanthin-J-yl. 2.6-dichloropurin-9-yl. 2.6-bis(methyIamino)purin-9-yl. 8-azaadenin-9-yl. 8azaguanin- 9-yl. 7-deazaadenin-9-yl. and the like;

each of R' and R" is hydrogen. hydroxy. alkoxy or 40 acyloxy;

each of R and R is hydrogen. hydroxy. alkoxy or acyloxy; and R and R together are acetal or ketal group. e.g. isopropylidenedioxy. p anisylidenedioxy. and the 5 like, the starting material is a nucleoside 5'- aldehyde and will be converted by reaction with the latter ylid using the process of the present in- 5 vention to the corresponding intermediary 5, 6' R ;P=CH dideoxyhex-S-enofuranosylnucleoside 6'- a Z2" phosphonate wherein 0 each ofZ' and Z is the rou OR". SR.

g P i -OH:CH R

. RH R1:

or NR 'R" in which I each of R and R" is lower alkyl. lower alkenyl. aryl 0 11nd '-en anosyl nucleoside 6'- or substituted aryl. and phosphonate. respectively each of R and R is lower alkyl: Z'" and Z together are the group if PCH=C1I R12 0 5 22/ /0 l R R9 wherein all substituents are as defined herein-above.

The intermediary afi-unsaturated phosphonates are converted by catalytic hydrogenation or diimide reduction as described herein-above to afford a corresponding saturated phosphonate. i.e.. nucleosidc bphosphonates having the formulas:

IlIT

HO (I? P-CHr-CH:

ca" m an n wherein all substituents are as defined hereinabove. For example. where each of Z and 2*" represents the group OR" in which R is lower alkyl. the alkyl groups are removed by heating with an iodide salt such as so dium iodide. in an aprotic dipolar solvent. such as dimethylformamide. at a temperature of about lC to l5UC for about 16 to 48 hours. Where each ofZ" and represents the group OR in which R is aryl or substituted aryl. the aryl or substituted aryl groups are removed by alkaline hydrolysis in a step-wise manner by reacting first at room temperature in an aqueous organic solution of a strong alkali metal hydroxide such as lithium hydroxide or sodium hydroxide in aqueous dioxane. tetrahydrofuran. acetonitrile. and the like. for about 30 minutes to 2 hours. The second OR group is removed by refluxing with saturated aqueous barium hydroxide solution for 30 minutes to two hours. Alternatively. the second OR'' group is removed by enzymatic action by incubation in the presence of a snake venom phosphodiesterase such as that present in the venom of ('miulcus urlumumem and the like. Where each ofZ' and 2" represents the group OR in which R is a lower alkenyl or aryl group. more specifically an allyl group. a benzyl group or a substituted benzyl group. the allyl. benzyl or substituted benzyl groups are removed by hydrogenolysis at room temperature over a palladium on an inert support catalyst such as a palladium-on-barium sulfate catalyst under a slight positive pressure of hydrogen for a period of about 2 to 6 hours. Where each ofZ and 2*" represents the group OR in which R is phenyl. substituted phenyl or naphthyl. the nucleoside 6'-phosphonic acid can be prepared by subjecting the nucleoside 6'-phosphonate to transesterification by treatment with a primary alcohol in dipolar organic solvent in the presence of a base followed by anionic dealkylation in the case of dialkyl phosphonates or hydrogenolysis in the case ofdiaralkyl phosphonates. Suitable primary alcohols include the saturated aliphatic alcohols such as methanol. ethanol. 2.2.l trichloroethanol. and the like of up to about six carbon atoms and aralkyl alcohols such as benzyl alcohol. methylbenzyl alcohol. B-phenylethanol. 3-phenyll-propanol. 4-phenyl-l-butanol. and the like. Suitable bases for generating the alkoxide or aralkoxide include the alkali metal hydrides. alkali metals. alkali metal I- butoxides, triethylamine. and the like. The reaction is carried out under anhydrous conditions in a dipolar organic solvent such as dimethylformamide. dimethylsulfoxide. and the like.

Where each of Z and 2"" represents the group SR in which each of R is lower alkyl. aryl or substituted aryl. the alkylthio. arylthio or substituted arylthio groups are removed in a stepwise manner by treatment with a mild alkali such as alkali metal bicarbonate or an alkali metal carbonate in an aqueous organic solvent such as aqueous methanol. acetone. and the like. at room temperature for a period of about 30 minutes to 6 hours to remove the first group and then by treatment with an aqueous acetone solution containing a molar equivalent of iodine to remove the second group. as described by A. Z. Nussbaum et al.. J. Am. Chem. Soc. 87 2513-4 1965 Where Z" and Z together represent the group in which R" is arylene such as o-phenylene. the o-ary lene group is removed in a step-wise manner by treatment with water to form an intermediary ohydroxyphenyl monoester and second by treatment with an aqueous solution of bromine, essentially hypobromus acid. to cleave the o-hydroxyphenyl group, as described by T. A. Khawaja and C. E. Reese. J. Am. Chem. Soc. 88. 3446-7 U966). Where each of Z' and 2*" represents the group the morpholinyl groups are removed by aqueous hydrolysis with an acidic ion-exchange resin such as sulphonated polystyrene beads cross-linked with 8% divinylbenzene or with an aqueous inorganic acid such as bydrochloric acid. Where each of Z"' and Z represents the group or NR R'. the piperidyl groups or the dialkylamino groups are removed by aqueous hydrolysis with an acidic ion-exchange resin in the acid form or with an aqueous inorganic acid such as aqueous hydrochloric acid.

Alternatively. removal of the Z' and Z groups can be effected by one of the procedures described hereinabove prior to the catalytic hydrogenation or diimide reduction procedure. as described hereinabove. to obtain the nucleoside o'phosphonic acids.

The novel phosphorylated phosphonium ylids of the present invention are versatile reagents useful in con verting carbonyl compounds into phosphonates. free phosphonic acids or phosphonic acid salts. They are useful as intermediates in the preparation of. for exam ple. insecticides. herbicides. oil additives. detergents.

lubricant and oil additives. flame retardants. antioxidants and nucleoside phosphonates. phosphonic acids and phosphonic acid salts. Insecticides such as the alkyl p-nitrophenyl alltylphosphonates and thio analogs thereof can be prepared by condensing acetalde hyde. propanal. butanal. and the like. with the appro priately substituted phosphorylated phosphonium ylid. namely wherein Y is oxygen or sulfur; Z is O-ethyl and Z is O-p-nitrophenyl. followed by reducing the intermediary a. B-unsaturated phosphonate or thiophosphonate by the diimide reduction. Herbicides such as the diesters of octylphosphonic acid can be prepared by condensing heptanal with the appropriately substi tuted phosphorylated phosphonium ylid. namely wherein Y is oxygen and each ofZ and Z is the group OR in which R is lower alkyl. aryl or substituted aryl followed by catalytic hydrogenation or diimide reduction of the intermediary a.B-unsaturated phosphonate. Oil additives such as the dialkyl styrylphosphonates can be prepared by condensing benzaldehyde with the ap' propriately substituted phosphorylated phosphonium ylid. namely wherein Y is oxygen and each of Z and Z is the group OR in which R is lower alkyl. The nucleoside b'-phosphonic acids prepared according to the process of this invention and derivatives prepared therefrom are isosteric with the natural nucleoside 5'- phosphates and derivatives thereof and can be used in the same manner as and as a replacement for the latter compounds. The nucleoside 6'-phosphonic acids and derivatives thereof differ from the known nucleoside 5'-phosphates and derivatives thereof in that the former contains a PCH C group in place of the natural P-OC group. thereby conferring greater metabolic stability to the former. The nucleoside 6- phosphonic acids and derivatives thereof are not sensi tive to cell wall phosphatase and hence are not cleaved into the parent materials during entrance into the cell. The nucleoside 6'-phosphonic acids and derivatives thereof are also useful intermediates for the prepara tion of cyclic 3'.6'-phosphonates. This conversion can be accomplished by treating the nucleoside 6'- phosphonic acid with a dehydrating agent. eg a carbodiimide such as N.N'-dicyclohexylcarbodimide. N.N'-di-p-tolylcarbodiimide. and the like in a basic solvent such as pyridine according to the procedure of Smith et al.. J. Am. Chem. Soc. 83. 698. (1961]; U.S. Pat. No. 3,300,479; French 2883M( l964); or French 3249M (1965). The cyclic 3',6'-phosphonates can be used in the same manner as and as a replacement for nucleoside cyclic 3.5'-phosphonates such as adenosine 3',5'-cyclic phosphate which are useful. for example. for the control of steroid production, the treatment of hypotension and as vasodilators. The cyclic 3,6'- phosphonates being much less susceptible to hydrolysis than are the cyclic 3 ',5-phosphates have the advantage of a longer biological half life.

The following examples are set forth to illustrate the present invention.

EXAMPLE I To a mixture of 7.14 g. (20 mmoles) of methyltriphenylphosphonium bromide in l00 ml. of ether. cooled to 20C and under a nitrogen atmosphere. is added I26 ml. of a 1.6M solution of n-butyl lithium in hexane (20 mmoles). The mixture is allowed to stand at 20C for additional V2 hour. at which time a yellow solution of methylenetriphenylphosphorane is present. To this mixture is then added dropwise a solution of 2.68 g. l0 mmoles) of diphenyl phosphorochloridate in 50 ml. of ether over a period of 5 minutes. and the resulting reaction mixture is allowed to stand for a period of 15 minutes. The reaction mixture is then extracted with two l00 ml. portions of 3N hydrochloric acid. The combined acid extracts are washed with ether. and then carefully neutralized by the dropwise addition of 4N aqueous sodium hydroxide to afford a precipitate. The precipitate is collected by filtration. washed with water and then hexane to yield diphenyl triphenylphosphoranylidenemethylphosphonate which is further purified by recrystallization from cthyl aceta te:hexane.

In a similar manner by repeating the above procedure with one exception. namely substituting first methyldiphenyl-tbutylphosphonium bromide, second tetrame' thylphosphonium bromide. third methyltricyclohexyl phosphonium bromide. and fourth dimethyldiphenylphosphonium bromide for methyltriphenylphosphonium bromide. there are generated in situ the corresponding intermediary monosubstituted phosphonium ylids first methylened phenyl-tbutylphosphorane. second methylenetrimethylphosphorane. third methylenetricyclohexylphosphorane.

and fourth methylenemethyldiphenylphosphorane for methylenetriphenylphosphorane in the above procedure, and there are obtained the corresponding diphenyl phosphor-anylidenemethylphosphonates. namely first diphenyl diphenyl-tbutylphosphoranylidenemethylphosphonate. second diphenyl trimethylphosphoranylidenemethylphosphonate. third diphenyl tricyclohexylphosphoranylidenemethylphosphonate. and fourth diphenyl methyldiphenylphosphoranylidenemethylphosphonate.

EXAMPLE 2 To a mixture of L78 g. of methyltriphenylphosphonium bromide in 25 ml. of ether. cooled to 20C and under a nitrogen atmosphere. is added 3.10 ml. of l.6M solution of n-butyl lithium in hexane. The mixture is allowed to stand at 20C for an additional /2 hour, at which time a yellow solution of methylenetriphenylphosphorane is present. To this mixture is then added dropwise a solution of 0.74 g. of di-o-tolyl ph0sphorochloridate in 10 ml. of ether. and the resulting re action mixture is allowed to stand at room temperature for a period of l5 minutes. The reaction mixture is then partitioned between 50 ml. of water and 50 ml. of benzene. The aqueous layer is separated and extracted with several portions of benzene. Then the combined organic phase and extracts are washed with water and dried over magnesium sulfate. After removing the magnesium sulfate by filtration. the organic phase is evaporated to dryness under reduced pressure to afford a colorless oil. The oil is recrystallized from ethyl acetate:- hexane to afford di-o-tolyl triphenylphosphoranylidenemethylphosphonate as a white crystalline solid.

l7 18 In a similar manner by repeating the abtove pIIroceduIreI Cminued ll i-m-ti wnh one excgptlon namely buhstltut ]& I "St I Phosphonium Salts Phosphorylating Products phosphorochloridate, second di-p-tolyl phosphoro- Agflm chloridat e. and third di-3,5-xylyl phosphorochloridate melhymiphcnw wmhwmhm mypynnm for the di-o-tol 'l hos horochloridate in the above rohos hoi'iium bromide phcnyl) pyrophosphatc phenyll tri- 3 P I I P I P P II I h I h cedure. there are obtained the corresponding diary] tn phenylphosphoranylidenemethylphosphonates. namely p hiifiphtmil lL di-m-tolyl triphenylphosphoranylidcneniethylphos- I I I I" D I'I II i w w i y II l env I. H phonate, di-p-tolyl triphenylphosphoranylidenemethyl- P MD C mg g :g phosphonate and di-3.5-xylyl triphenyl phosphoranyln ,lt) II I I nihiispIhonatc r t methyltriphenyli-(p-brominen/y iip romodenemeth) lphosphohphonine' phosphonium bromide phosphorochloridati: beii/yl) triphcnyL phosphonmy lidenemethylphosphonatc EXAMPLE 3 methyltriphenyldiphenyl phosphorodiphenyl tri I I phosphonium bromide chloridothioate phenylphosphor- To I00 ml. of anhydrous liquid ammonia, previously nyli n hylthiophosphonati: cooled in a Dry Ice acetone bath and under an inert at memIvmIphmyL diIwInimIhen/IU diIIPMimII p r f rg n. are added g of l i Sodium phosphonium bromide phosphorochloridate benzlyll triphenyland a few grains of ferric nitrate, and the resulting mixe i s ture is allowed to stir until it turns grey. Then 3.57 g. melhImiphenyL Wphmykne PMS mphenylcne m l0 mmoles) Of methyltriphenylphosphonium bromide phosphoiiium bromide phorohromidate phe Ii alphosphIorI- is added to the mixture. After stirring the mixture for 15 minutes. the ammonia is removed by evaporation methyltriphciiyllj-dimeih iinlldimcthyltrileaving behind a residue To this residue is then added phosphunium bromide methylene phosphoromhethyIlcile tr;I-

chloridati: p en p osp or 100 ml. of anhydrous tetrahydrofuran, and the resultai lidencmcihyling mixture is held at reflux for 20 minutes to expell any 35 l residual ammonia, then cooled and filtered through a sintIered gdlgssdfiitezzof mesdium riorositfyhd'fohtheIfiltgate EXAMPLE 4 is t en a e g. mmo es) 0 ip eny p 05- phorochloridate and this mixture is then held at room To 9 f mmdmus hqu'd prfilmusll temperature for a perind of minutesI The reaction 30 cooled in a Dry lee-acetone bath and under an inert atmixture is then filtered and the filtrate evaporated to zI P f i 1rg0nf.fare -added 0.5 gdofhmetalliIc sodiu m dryness to yield diphenyl tripheriylphosphoranylidene 2 g i e fir g g methylphosphonate which is further purified by recryswe Owe 0 S l urns grey en wmzation from ethyl acmalehexzme l0 mmoles) of methyltriphenylphosphoriium bromide In I similar manner y repeating the above pmsedure is added to the mixture. After stirring the mixture for [5min r with the phosphonium salts and phosphorylating agents lcavin gs i gi $2333??? L L Z TS E T AZ S indicated in the table. there are obtained the following g s n a e mducw lUO ml. of anhydrous tetrahydrofuran and the resultp ing mixture is held at reflux for 20 minutes to expell any 40 residual ammonia. then cooled and filtered through a sintered glass filter of medium porosity. To the filtrate Phosphoniuni Salts Phosphorylating Products is then added 1.27 g. (5 mmoles) Of phosphorodimor Agem pholidic chloride and this mixture is then held at 40C ethyltriphcnylphosdiphenylphosphorodiphenyl ll-trifor a perlod of l hourv The reaction mlxture 15 l phonium bromide Chloridate phenylphosphortered and the filtrate evaporated to dryness to yield tri phenylphosphoranylidenemethylphosphonodimormethyltriphenylphosdielhyl phosphoriidiethyl tripholidate which is further purified by recrystallization phonium bromide chloridate f ethyl acetate: hexanI phlmphmm In a similar manner by repeating the above procedure i' P fl p l' melhyltliwith the phosphonium salts and phosphorylating agents chloridute phenylphosphoranylidenemethylphosphonati:

phosphonium bromide indicated in the table. there are obtained the following products:

methyltriphenylphosphom'um bromide methyltriphenylphosphonium bromide tetramethylphosphonium bromide methyltri-n-butylphosphonium bromide N N dimethylphosphorodianalidic chloride 0.0-di henyl phosphoroc loridothioate 0,0 diphenyl phos phorochloridothio- 81 phosphorodimorpholidic bromide methylthiophosphonate triphenylphosphoranylidenemeihylphosphonodi(Nmethylanilidate] diphenyl triphenylphosphoranylidenemethylthiophos honate diphenyl trimet yl pb0sphoranylidenemethylthiophosphonate tri-nbutylphosphoranylidenemethylphosphonodimorpholidate EXAMPLE To 100 ml. of anhydrous liquid ammonia. prc\ iously cooled in a Dry lee-acetone bath and under an inert atmosphere of argon. are added 0.5 g. of metallic sodium and a few grains of ferric nitrate. and the resulting mixture is allowed to stir until it turns grey. Then 4.34 g. it) mmoles) of benzyltriphenylphosphonium bromide is added to the mixture. After stirring the mixture for minutes. the ammonia is removed by evaporation leaving behind a residue. To this residue is then added 100 ml. of anhydrous tetrahydrofuran. and the resulting mixture is held at reflux for minutes to expell any residual ammonia. then cooled and filtered through a sintered glass filter of medium porosity. To the filtrate is then added 1.3-1 g. [5 mmoles) of diphenyl phosphorochloridate and this mixture is then held at 65C fora period of 2 hours. The reaction mixture is then filtered and the filtrate evaporated to dryness to yield diphenyl triphenylphosphoranylidenebenzylphosphonate which is further purified by recrystallization from ethyl acetatezhexane.

Products Phosphonium Salts Phosphorylating Agents EXAMPLE 7 To a solution of 2.84 g. (10 mmoles) of 2'.3'-O- isopropylideneuridine in ml. of anhydrous dimethyl sulfoxide are added 6.2 g.( mmoles) of dicyclohexylcarbodiimide. 0.8 ml. [lU mmolesl of pyridine and ()4 ml. (5 mmolesj of trifluoroacetic acid. The result ing solution is allowed to stand at 25C for 6 hours. dur ing which time dicyclohexylurea precipitates from the solution. At the end of the reaction. dicyclohexylurea is removed by filtration and Washed with several portions of fresh. anhydrous dimethyl sulfoxide. To the combined filtrate and washings. is added 5.08 g. (it) mnioles) of diphenyl triphenylphosphoranylidenemethylphosphonate. and the resulting mixture is allowed to stand at 37C for [6 hours. At this point. 200 ml. of ethyl acetate is added. and the organic phase is washed with three IOU ml. portions of water. dried. filtered. and evaporated under reduced pressure to afford a pale yellow oil. A solution of the thus obtained oil in chloroform is chromatographed on eight 1 meter X 20 cm. glass plates coated with a l.3 mm. layer ofsilicic acid. After development of the plates with ethyl acetate. two ultraviolet absorbing products are eluted from the plates with ethyl acetate. After removing the solvent from the faster moving product, there is obtained diphenyl [l-( 5.o-dideoxy-l.3O-isopropylidene-B-D- ribo-hex-5enofuranosyl)uracil] 6'-phosphonate which is purified by recrystallization from aqueous ethanol. After removing the solvent from the slower moving product. there is obtained triphenylphosphine oxide.

benzyltriphenyl phosphonium bromide benzyld imethylphenyh phosphonium bromide p-nitrohenzyltriphenylphosphonium bromide diethyl phosphorochloridate diphenyl phosphorochloridate diphenyl phosphorochloridothid ate diethyl triphenyl phosphoranylidene benzylphosphonate diphenyl dimethylphenylphosphoranylidenebenzylphosphoriate diphenyl triphenylphosphoranylidenep-nitrobenzylthid di-p-tolyl phosbenzyltricyclohexylphorochloridate phosphonium bromide EXAMPLE 6 A mixture of 0.36 g. (I mmole) of Z'.3'-O- anisylideneuridine-S'-a|dehyde [prepared in accordance with LKS. Pat. No. 3.248.380] and 0.508 g. (l mmole) of diphenyl triphenylphosphoranylidenemethylphosphonate in [U m]. of tetrahydrofuran is allowed to stand at 37C for a period of 16 hours. The reaction mixture is then chromatographed on a 1 meter X 21 cm. glass plate coated with a l} mm. layer of silicic acid. After duelopment of the plate in the solvent mivture. isopropanol:chloroform [:9). the main ultraiolet absorbing band (Rf (1.5) is eluted with acetone. After removing the solvent by evaporation under reduced pressure. there is obtained diphenyl (1423-0- anisylideneSb-dideoxy-B-D-ribo-hexfienofuranosylJuracill 6'-phosphonate as a white. homogeneous foam.

In a similar manner by repeating the above procedure with two exceptions. namely substituting a molar amount of each of 2'.3'-O-isopropylideneadenosine and diethyl triphenylphosphoranylidenemethylphosphonate for 2',3'-O-isopropylideneuridine and diphenyl triphenylphosphoranylidenemethylphosphonate. respectively. there is obtained the corresponding product. namely diethyl [9-(5.6-dideoxy-2.3-O- isopropylideneBD-ribohex-5-enofuranosyl )adenine] 6-phosphonate.

EXAMPLE 8 A solution of5 l 2 mg. (l mmole i of diphenyl l-(5.6- dideoxy2.3-O-isopropylidene-BD-ribo-hex-S- enofuranosyl )-uracil} 6'-phosphonate in 30 ml. of methanol is hydrogenated at 20C in the presence of 0.2 g. of a pre-reduced 5% palladiumon-barium sulfate catalyst and under a slight positive pressure of hydro gen for two hours. at which time. the uptake of hydrogen reached the theoretical value. The catalyst is removed by filtration through diatomaceous earth and washed with methanol. The combined filtrate and washings are evaporated to dryness under reduced pressure to yield diphenyl [1-15.6-dideoxy-l3-O- isopropylidene-B-D-ribo-hexofuranosyl )uracill n phosphonate as a white foam.

In a similar manner by repeating the above procedure with one exception. namely substituting a molar amount of diethyl l9-t5.h-dideoxy 2.3()- isopropy'lidene-B-ribo-hex-5-enofuranosyl )-adeninc] 6'-phosphonate for diphenyl [l-(5.o-dideoxy-2.3-O- isopropylidene-B-D-ribo-hex-5-enofuranosy)uracil] 6'-phosphonate. there is obtained the corresponding product. namely diethyl [9-(5.6-dideoxy-2.3-O- isopropylidene-B-D-ribo-hexofuranosylJadenine] 6 phosphonate.

EXAMPLE 9 A solution of0.50 g. of diphenyl I l-( 5.6-dideoxy-l3- O-isopropylidene-B-Dribo-hexofuranosyl)uracil] 6- phosphonate in 20 ml. of 80% acetic acid is heated at 100C for 2 hours. The solvent is then removed by evaporation under reduced pressure to yield a residue of diphenyl [1-( Sb-dideoxy-B-D-ribohexofuranosyl )uracill 6'-phosphonate which is purified by repeated dissolution and evaporation from several quantities of ethanol.

In a similar manner by repeating the above procedure with one exception, namely substituting diethyl (9- (5 ,o-dideoxy 2.3-O-isopropylideneB-D-ribohexofuranosyl)adenine] 6-phosphonate for diphenyl I l-( 5 .o-dideoxy-2.3-O-isopropylidene-B-D-ribohexofuranosyl)uracil] 6'-phosphonate. there is obtained the corresponding product. namely diethyl 19- (5,6-dideoxy-B-D-ribo hexofuranosyl)adenine] 6' phosphonate.

EXAMPLE 10 To a solution of 119 mg. (0.25 mmole) of diphenyl 1 14 5.b-dideoxy-B-D-ribo-hexofuranosyl)uracil] 6'- phosphonate in 10 ml. of dioxane and 10 ml. of water is added 1 ml. of 1N aqueous solution of lithium hydroxide. The resulting solution is allowed to stand at C for 1 hour at which time the pH of the solution is adjusted to 7 by the addition of an acid-ion exchange resin. After removing the resin by filtration. the filtrate is reduced to dryness under reduced pressure to afford a residue. A solution of the thus-obtained residue in 10 m1. of water is chromatographed on a 1 meter x 20 cm. glass plate coated with a 1.3 mm. layer of microcystalline cellulose. After developing the plates in the solvent mixture. isopropanol:ammonium hydroxide:water (7:122). the ultraviolet absorbing material, having an EXAMPLE 11 One milliliter of a solution containing 40 mg. (0.1 mmole) of phenyl l 1-( 5,6-dideoxy-[3 D-ribohexofuranosylmracil] 6-phosphonic acid, ;;1. of 0.0lM aqueous magnesium chloride, 40p.l. of a solution containing 10 mg/ml. of crude Crowleus adamantens venom in 0.5M tris(l1ydroxymethyl )aminomethane buffer at pH 8. 4011.1. of a 1M tristhdyroxymethyl )aminoethane buffer at pH 8. is incubated at 37C for 24 hours. After this reaction time. the incubation mixture is then diluted with 25 ml. of water and chro matographed on a 1.5 X 20 cm. column containing 25 g. of diethylaminoethyl cellulose in the bicarbonate form. The column is washed with 200 ml. of water and then eluted with a linear gradient ((1.002 -0.2M) of aqueous triethylammonium bicarbonate at pH 7.5. The main ultraviolet absorbing peak is collected and emporated to dryness under reduced pressure to yield the bistriethylammonium salt ofl l'(5.b-dideoxy-B-D-ribohexofuranosyl )uracil] 6-phosphonie acid.

EXAMPLE 12 By repeating the procedure of Example 7 with two exceptions. namely substituting 3'-O-acetylthymidine and dibenzyl triphenylphosphoranylidenemethylphosphonate for 2',3-O-isopropylideneuridine and di phenyl triphenylphosphoranylidenemethylphosphon ate. respectively, there is obtained dibenzyl [1-(3-0- acetyl-2.5,o-trideoxy-fi-Derythro-hex-5- enufuranosyl)thymine] 6'-phosphonate.

EXAMPLE 13 A solution of 0.54 g. of dibenzyl [l-(3-O acetyl- 2,5,o-trideoxy-B-D-erythro-heX-S' cnofuranosyl)thymine] (J'-phosphonate in 25 ml. of methanol is reduced at 25C in the presence of 200mg. of a pre-reduced 571 palladium-on-barium sulfate catalyst and under a slight positive pressure of hydrogen for a period of three hours. The catalyst is removed by filtration through diatomaceous earth. and washed with methanol. The combined filtrate and washings are evaporated to dryness under reduced pressure to yield 1-( 3-O-acety1-2,5.o-trideoxy-fl-D erythrohexofuranosyl)thymine] 6'-phosphonic acid.

A solution of the 0.5 g. of the latter material in 5 ml. of concentrated ammonium hydroxide is held at 25C for a period of 30 minutes. After removing the solvent by evaporation under reduced pressure. the residue is chromatographed on a 3.0 X 30 cm. column of diethylaminoethyl cellulose in the bicarbonate form. The column is washed with 250 ml. of water and then eluted with a linear gradient (0.0020.2M) of aqueous triethylammonium bicarbonate at pH 7.5. The major ultra violet absorbing peak is collected and evaporated to dryness under reduced pressure to yield the bistriethylammonium salt of [l-(2.5.6-trideoxy-B-D-erythrohexofuranosyhthymine] 6-phosphonic acid.

EXAMPLE 14 A mixture of 1.76 g. of diethyl 19-[5.6-dideoxy-2.3- O-isopropylidene-B-D-ribohexofuranosyl)adenine] 6'- phosphonate and 1.8 g. of sodium iodide in 10 ml. of dimethylformamide is heated at 150C for 20 hours. After cooling the reaction mixture. there is added 50 ml. of acetone. The resulting precipitate is collected and washed with several portions of acetone. The precipitate is then dissolved in water and passed through a column containing the free acid-form of an ionexchange resin. The thus-obtained acidic eluate is concentrated under reduced pressure to one-half the original volume and then heated at C for 4 hours to give an aqueous solution of [9-(5.6-dideoxy-B-D-ribohexofuranosyhadenine] 6'-phosphonic acid. For purification. if desired. the pH of the eluate is adjusted to 8.5 with aqueous sodium hydroxide solution and the resulting mixture is chromatographed on 114.0 X 40 cm. column ofdiethylaminoethyl cellulose in the bicarbon ate form using a linear gradient ((1.002 to (1.2M J of trie thy lammonium bicarbonate as eluant to afford the bistrietbylammonium salt of [94 5.h-dideoxy-fi-D-ribohexofuranosyl )adeninel o'phosphonic acid.

An aqueous solution of the latter compound is passed through a column ofcation-exchange resin in the acidform. and th pH of the eluate is adjusted to 8.5 by the dropwise addition of aqueous sodium hydroxide solution. The eluate is then concentrated to a volume ofapproximately ltl ml.. and added to 50 ml. of acetone to yield the disodium salt of |9 5.otlidct)xy"B-D-ribo hexofuranosyl)adeninel o-phosphonic acid as a white powder.

EXAMPLE To a mixture of 5l2 mg. (l mmole) of diphenyl I l (5.b dideoxy-IB-O-isopropylidene-B-D-ribo-hex-S- enoluranosylluracill 6'-phosphonate. 500 mg. of potassium azodicarboxylate in ml. of methanol. is added dropwise 300 mg. of glacial acetic acid. and the reaction mixture is held at room temperature for a period of 24 hours. After this reaction time. the mixture is evaporated to dryness under reduced pressure and the residue partitioned between 50 ml. of ethyl acetate and 50 ml. ofvvater. The aqueous layer is separated and extracted with several portions of ethyl acetate. The combined ethyl acetate layer and extracts are dried over magnesium sulfate. evaporated to dryness under reduced pressure to yield diphenyl ll-(5.6-dideoxy 2.3-O-isopropylidene-B-D-ribo-hexofuranosyl)uracil] h'phosphonate.

In a similar manner. by repeating the procedures of Examples 9. l0 and ll. the latter material is converted to the his triethylatnmonium salt of l l[5.o-dideoxy-B- D-ribtrhexofuranosyl)uracill o'-phosphonic acid.

EXAMPLE lb A mixture of92.7 g. of triphenylphosphine and l()().l g. diphenyl chloromethylphosphonate is heated at 175 for N2 hours. The resultant solid mass is dissolved in about [700 ml. water and about 500 ml. ether and the phases are separated. The ether layer is further extracted with about 250 ml. water. The combined aqueous phases are brought to pH 8 by the cautious addition of ll) N sodium hydroxide and the precipitate removed by filtration and dried to give diphenyl triphenylphosphoranylidenemethylphosphonate which is crystallized from ethyl acetate.

EXAMPLE l7 A solution of5tl8 mg. ofdiphenyl triphenylphosphor anylidenemethylphosphonate in It) ml. of methanol is heated under reflux for minutes. Removal of the methanol by evaporation under reduced pressure giv es a residual syrup which is crystallized from a mixture of ethyl acetate and hexane to give dimethyl triphenylphosphoranylidenemethylphosphonate.

EXAMPLE [8 To a stirred mixture of 4.82 g. (9mmole) ofdiphenyl [9-(5.6-dideoxy-2.3-O-isopropylidene-B'D-ribQ-heX-S- enofuranosyl)adenine} 6'-phosphonate and 9.0 g. of potassium azodicarboxylate (45 mmole) in I ml. of

Ill

pyridine is added 54 g. of glacial acetic acid mmole]. The yellow suspension is stirred under anhydrous conditions in an argon atomosphere for 24 hours and then the pyridine is removed by evaporation under reduced pressure. The yellow residue is partitioned be tween water (250 ml.) and ethyl acetate (250 ml.) and the water phase is further extracted with ethyl acetate [2 X 250 ml.). The organic phase are combined. washed with water (500]. dried over magnesium sulfate. filtered and evaporated to dryness to give a pale yellow foam. This is dissolved in about 20 ml. of hot benzene and on cooling deposits white crystals which are collected to give diphenyl (9-1 5.6-diodeoxy-l3-oisopropylidene-B-D-ribo-hexofuranosyl )adenine] o'- phosphonate.

EXAMPLE 1) A solution of 5. 14 g. 1U mmole ofdiphenyl H 5.6- dideoxy-Z.3-O-isopropylidene-- D-ribo-hexofuranosylJuracil] 6'-phosphonate in 50 ml. of dimethyl sulfoxide is added rapidly at room temperature to a solution of 2.0 g. (42 mmoles) of sodiuim hydride (5092 dispersion in mineral oil) in 20 ml, each of benzyl alcohol and dimethyl sulfoxide. After l5 minutes, the slightly yellow solution is poured into 250 ml. of water containing 3 ml. of glacial acetic acid. The re sulting suspension is extracted with ethyl acetate (3 X 200 ml.) and the combined extracts are washed with aqueous sodium bicarbonate and then water. The or ganic phase is then dried over magnesium sulfate. filtered and evaporated to dryness to give a pale yellow oil. A solution of this oil is chloroform (25 ml.) is then applied to the top ofa silica gel column (35 X 4.5 cm.J. Development of the column with 1250 ml. chloroform and 650 ml. of ethyl acetate followed by elution with 1000 ml. 10 /r methanol in ethyl acetate gives dibenzyl [1-( 5.6dideoxy2.3-O-isopropylidene-B-D-ribohexofuranosyl)uracil] 6'-phosphonate.

EXAMPLE 20 A solution of 4.52 g. of dibenzyl [l( 5.6-dideoxy-2.3- O-isopropylidene-B-D-ribo-hexofuranosyl)uracil] 6- phosphonate in lOO ml. of methanol is added to a prereduced suspension of 2 g. of 5% palladium-on-barium sulfate in [00 ml. of methanol. The resultant mixture is stirred at room temperature under l atmosphere of hydrogen for 50 minutes at which time the theoretical volume of hydrogen has been consumed. The catalyst is removed by filtration through diatomaceous earth and the combined filtrate and washings are evaporated to dryness to yield a white foam which is redissolved in 50 ml. of water. The aqueous solution is passed down an acid ionexchange columne (2.5 X 20 cm.) which is washed with water. The first 225 ml. of column eluant is heated at C for l hour and then evaporated to dryness under reduced pressure. The residue is reevaporated several times from methanol solution and is then dissolved in 50 ml. of hot ethanol. The solution on cooling deposits a white microcrystalline solid to yield [l- (5 .6-dideoxy-B-D'ribo-hexofuranosyl )uracil] 6 phosphonic acid.

EXAMPLE 21 The proces of Example 7 is repeated using an equivalent amount of l-(N ,O -tribenzoyl-BD- arabinofuranosylj cytosine as the starting material and there is obtained diphenyl [l-(5,6-dideoxy N 0 25 -tribenzoyl-B-D-arabino-heicfienofuranosyl)cylosine] 6'-phosphonate. This conver sion can be illustrated as follows wherein B represents benzoyl and d) is phenyl:

ITHB ryma N N O l O ll H()CH: O N H N I 0B B OH in;

NHB

Similarly. by using l-(2'.3'-di-O-benzoyl-B-D- arahino-furanosyl)thymine and l-(2'.3'-di-o-benzoyl- B-D-arabinofuranosyl)uracil in the process of Example 7. there is obtained diphenyl ll-(5,6 dideoxy-2',3'-di- O-henzoyl-B-D-arabino-hex-S-enofuranosyl)thymine] 6'-phosphonate and diphenyl l-(5.6-dideoxy-Z'.3'di O-hcnzoyl-B-D-arabino-hex-5-enofuranosyl)uracill 6'- phosphonate. respectively.

By repeating the process of Example 18. the above compounds are reduced to the corresponding arabinohexofuranosyl derivatives, that is, diphenyl ll-(5,6- dideoxy'-N,O -tribenzoyl-B-D-arabinohexofuranosyl)cytosine] 6'-phosphonate. diphenyl l l- (5.6-dideoxy-2',3'-di-O-benzoyl-B-D-arahinohexofuranosyl)thyminel b'phosphonate and diphenyl I l-( 5.6-dideoxy-2',3'-diO-benzoyl-B-D-arabinohexofuranosyl)uracill 6'-phosphonate which are subjected to the processes of Examples 19 and 20 to give [l-( 5.6-dideoxy-B-D-arabino-hexofuranosyl )cytosinel 6-phosphonic acid. l-(5.o-dideoxy-fi-D-arabinohexofuranosyl)thymine] 6'-phosphonic acid and l l- (5.6 dideoxy-B-D-arabino-hexofuranosyl)uracil] 6'- phosphonic acid.

EXAMPLE 22 The process of Example I) is repeated using an equivalent amount of diphenyl [9-(5.6-dideoxy-2.2-O- isopropylidene-B-D-ribo-hexofuranosyl)adeninel phosphonate and diphenyl ll-(3-O-acetyl-2.5.6- trideoxy-B D-crythro-hexofuranosyl)thymine] 6- phosphonate as the starting material and there is obtained dibenzyl [9-l5.6-dideoxy-2.3'O-isopropylidene- B-D-ribo-hexofuranosylJadenine] 6-phosphonate and dibenzyl l-( 3-O-acetyl-2.5.b-trideoxy-B-D-erythrohexofuranosyl)thyminel 6-phosphonate. respectively. which are subjected to the process of Example 20 to yield l9-(5.6-dideoxy-B-D-ribohexofuranosylladenine] 6'-phosphonic acid and {l- (2,5 .b-trideoxy-B-D-erythro-hexofuranosyl )thyminel 6-phosphonic acid. respectively.

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EXAMPLE 23 The process of Example 19 is repeated with the exception of using an equivalent amount of methanol in place of benzyl alcohol and there is obtained dimethyl l l-( 5.hdideoXy-ZJ-O-isopropylidene-B-D-ribohexofuranosyl )uracill 6-phosphonate.

Similarly. by using ethanol there is obtained diethyl l 5 .o-dideoxy2.3O-isopropylidene-B-D-ribohexofuranosyl luracil] 6'-phosphonate.

By subjecting the above compounds to the dealkylation procedure of Example 14. there is obtained the disodium salt of l (5.6-dideoxy-B-D-ribohcxofuranosyl )uracil] 6'-phosphonic acid.

What is claimed is:

l. A process for preparing 5'.6'-dideox v-hex-5'- enonucleosides o'-phosphonates. which comprises reacting a nucleoside 5'-aldehyde selected from the group having the formulas:

and

wherein R is selected from the group consisting of uracill-yl. Cytosin-Lyl. 4-chloro-l.Z-dihydropyrimidin- Z-on-l-yl. S-bromouracil-l-yl. S-hromocytosinl-y]. S-ChlOfOUl'tlCil-lfl'l. fi chlorocytosin-l yl. 5- iodouraciLl-yl. S-iodocytosin-l-yl. 5-fluorouracill-yl. S-t'luorocytosinl -yl. thyminl -yl. 5- methylcytosin-l-yl. 5-trifluoromethyluracill-yl. 5-trifluoromethylcytosin-l-yl. SaIniinouraciI-l-yl. S-aminocytosin-l-yl. S-methylaminouracil-l-yl. 5 methylaminocytosin-l-yl. S-hydroxyuracil-l-yl. 6- azauracil-l-yl. b-azacytosin-Lyl. 4-chloro-6-azal.Z-dihydropyrimidin-Z-on-l-yl. o-azathymin-l-yl. hypoxanthin-9-yl. adenin-9-yl, 6- dimethylaminopurin-9-yl, 2chloroadenin-9-yl. 6- chloropurin-Q-yl. 6-mercaptopurin-9-yl. guanin- 9-yl. xanthin-9-yl. 2.6-dichloropurin-9-yl. 2.6- bistmcthylamino)purin-9-yl, 8-azaadenin-9-yl. 8- azaguanin-J-yl. and 7-deazaadenin-9-yl; and

R. R"' R". and R are independently selected from the group ofhydrogen. hydroxy. methoxy. acetoxy. and

benzoyloxy, 0r

R and R together form acetal. isopropylidenedioxy or p-anisylidenedioxy with a phosphorylated ylid having the formula wherein R. R" and R are independently selected from the group of lower alkyl having from I to 6 carbon atoms. aryl having from 6 to 12 carbon atoms. or substituted aryl selected from the group of p- 27 chlorobenzyl. p-bromobenzyl 2.4,6- trichlorophenyl. p-nitrophenyl. p-nitrobenzyl. panisyl. p-methoxybenzyl. and pdimethylaminophenyl or R. R" and R together are tri-N-piperidyl. tri-N morpholinyl. or tricyclohexyl: and

Z and 2 are independently selected from the group of OR". SR"t or NR R" in which R and R are independently selected from the group of lower alkyl having from I to 6 carbon atoms. lower alkenyl having from 2 to 6 carbon atoms. aryl having from 6 to 12 carbon atoms or substituted aryl as defined herein above. and

R" and R are independently lower alkyl having from l to ocarbon atoms or Z' and Z together form the group in which R" is arylene having from 6 to 12 carbon atoms: in a substantially anhydrous non-reactive organic solvent under reactive conditions thereby forming the cor responding 5'.6'-dideoxy-hex-5'-eno-nucleoside 6'- phosphonate.

2. A process for preparing 6'-phosphonic acid nucleosides which comprises reacting a 6'-phosphonite nucleoside selected from the group having the formulas 2'" and Z1 R",

i it: I 1 I wherein 28 9-yl. xanthin-Q-yl. 2.6-dichloropurin9-ylt 2.6- bistmethylamino)purin-Q-yl, 8-azaadenin-9-yl. 8- azaguanin-J-yl, and 7-deaZaadenin-9-yl; and R, R', R". R' are independently selected from the group of hydrogen. hydroxy; methoxy, acetoxy, and benzoyloxy, or

R" and R together form acetal isopropy'lidenedioxy or p-anisylidenedioxy; and

Z and 2*" are each the group OR' wherein R is selected from the group of phenyl. toluoyl.

2,4.o-trichlorophenyl. p-nitrophenyl. p-

dimethyla ninophenyl and naphthyl with an aryl alkyl primary alcohol selected from the group of benzyl alcohol or methyl benzyl alcohol in the presence of a base selected from the group of alkaline metal hydrides alkali metals alkali metal t-butoxies. and triethylamine, in an aqueous dipolar organic solvent thereby yielding the corresponding diarylalkyl nucleoside 6'-phosphonate and hydrogenating said diary lalky'l nucleoside 6'-phosphonate in the presence of a hydrogenoly'sis catalyst under reactive conditions thereby yielding the corresponding nueleosides 6- phosphonic acid.

3. The process according to claim 1 wherein each of Z and Z is the group OR in which R is phenyl;.

4. The process according to claim 3 wherein each of R',.R and R" is phenyl.

5. The process according to claim 2 wherein said nucleoside 6'phosphonate is a diphenyl nucleoside 6- phosphonate, said alcohol is benzyl alcohoL said base is an alkali metal hydride and said catalytic hydrogenol ysis is carried out with a palladium catalyst.

6. The process of claim 1 wherein said 5-aldehyde nucleoside has the formula:

M in wherein R is as defined in claim 1 and R and R" are each acetoxy or together form the group isopropylidenedioxy or p-anisylidenedioxy, 7. The process of claim 1 wherein said 5' aldehyde nucleoside has the formula:

O CH R wherein R' is as defined in claim 1 and R and R" are each benzoyloxyv 8. The process of claim 1 wherein said reaction is conducted at temperatures in the range of about from 25C to the reflux temperature of said organic solvent. l 

1. A PROCESS FOR PREPARING 5'',6''-DIDEOXY-HEX-5''ENONUCLEOSIDES 6''-PHOSPHONATES, WHICH COMPRISES REACTING A NUCLEOSIDE 5''-ALDEHYDE SELECTED FROM THE GROUP HAVING THE FORMULAS:
 2. A process for preparing 6''-phosphonic acid nucleosides which comprises reacting a 6''-phosphonite nucleoside selected from the group having the formulas
 3. The process according to claim 1 wherein each of Z1'''' and Z2'''' is the group OR5 in which R5 is phenyl;.
 4. The process according to claim 3 wherein each of R1, R2 and R3 is phenyl.
 5. The process according to claim 2 wherein said nucleoside 6''-phosphonate is a diphenyl nucleoside 6''-phosphonate, said alcohol is benzyl alcohol, said base is an alkali metal hydride and said catalytic hydrogenolysis is carried out with a palladium catalyst.
 6. The process of claim 1 wherein said 5''-aldehyde nucleoside has the formula:
 7. The process of claim 1 wherein said 5''-aldehyde nucleoside has the formula:
 8. The process of claim 1 wherein said reaction is conducted at temperatures in the range of about from 25*C to the reflux temperature of said organic solvent. 